Hepatopulmonary syndrome and portopulmonary hypertension: A report of the multicenter liver transplant database



Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PortoPH) are pulmonary vascular consequences of advanced liver disease associated with significant mortality after orthotopic liver transplantation (OLT). Data from 10 liver transplant centers were collected from 1996 to 2001 that characterized the outcome of patients with either HPS (n = 40) or PortoPH (n = 66) referred for OLT. Key variables (PaO2 for HPS, mean pulmonary artery pressure [MPAP], pulmonary vascular resistance [PVR], and cardiac output [CO] for PortoPH) were analyzed with respect to 3 definitive outcomes (those denied OLT, transplant hospitalization survivors, and transplant hospitalization nonsurvivors). OLT was denied in 8 of 40 patients (20%) with HPS and 30 of 66 patients (45%) with PortoPH. Patients with HPS who were denied OLT had significantly worse PaO2 compared with patients who underwent transplantation (47 vs. 52 mm Hg, P < .005). Transplant hospitalization survival was associated with higher pre-OLT PaO2 (55 vs. 37 mm Hg; P < .005). MPAP was significantly higher (53 vs. 45 mm Hg; P < .015) and PVR was significantly worse (614 vs. 335 dynes · s · cm−5; P < .05) in patients with PortoPH who were denied OLT compared with patients who underwent transplantation. Transplant hospitalization mortality was 16% (5/32) in patients with HPS and 36% (13/36) in patients with PortoPH. All of the deaths in patients with PortoPH occurred within 18 days of OLT; 5 of the 13 deaths in patients with PortoPH occurred intraoperatively. We concluded that patients with HPS (based on a combination of low PaO2 and nonpulmonary factors) and patients with PortoPH (based on pulmonary hemodynamics) were frequently denied OLT because of pre-OLT test results and comorbidities. For patients who subsequently underwent OLT, transplant hospitalization mortality remained significant for both those with HPS (16%) and PortoPH (36%). (Liver Transpl 2004;182:10.)

In 1996 a cooperative, multicenter effort was initiated to address the issue of orthotopic liver transplantation (OLT) in patients with either hepatopulmonary syndrome (HPS) or portopulmonary hypertension (PortoPH).1 Specifically, by using standardized diagnostic criteria applied to any patient evaluated for OLT, we collected data to characterize the arterial oxygenation abnormality of HPS and pulmonary hemodynamics in PortoPH. All patients with either HPS or PortoPH were categorized by 3 mutually exclusive outcomes: (1) denied OLT; (2) underwent transplantation, but died during the same hospitalization; and (3) underwent transplantation with subsequent dismissal from the hospital.

Mortality associated with OLT in the setting of HPS2–5 or PortoPH5–8 is not insignificant. Therefore, it has been clinically relevant to identify prognostic factors associated with successful OLT in the setting of these pulmonary vascular consequences of liver disease.5, 6 We hypothesized that patients denied OLT had worse pretransplant oxygenation (in the case of HPS) or pulmonary hemodynamics (in the case of PortoPH) than those who underwent transplantation. In addition, we hypothesized that patients who survived the transplant hospitalization had better pretransplant oxygenation (HPS) or pulmonary hemodynamics (PortoPH) than patients who died during the transplant hospitalization. This article summarizes selected results pertinent to these hypotheses from our database that characterized 40 patients with HPS and 66 patients with PortoPH reported by 10 liver transplant centers.


HPS, hepatopulmonary syndrome; PortoPH, portopulmonary hypertension; OLT, orthotopic liver transplantation; MPAP, mean pulmonary artery pressure; CO, cardiac output; PWCP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; EtOH, ethanol; HCV, hepatitis C virus; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.


From 1996 to 2001, data were collected by use of an 8-page written questionnaire after institutional review board approval was obtained from 10 centers. Confidential data (coded so only the originating center knew specific patient identity) were submitted to the Mayo Clinic Section of Biostatistics and stored electronically. Diagnostic criteria for HPS and PortoPH are shown in Table 1. A total of 117 questionnaires were submitted; data from 11 questionnaires were deemed incomplete in terms of oxygenation (HPS) or hemodynamic (PortoPH) variables. Data from 106 patients were finally accepted and entered into the database. Operating room records were not reviewed. All liver transplant candidates were screened appropriately for HPS and PortoPH.

Table 1. Diagnostic Criteria
  • Abbreviations: HPS, hepatopulmonary syndrome; PaO2, partial pressure for arterial oxygen; Tc, technetium; PortoPH, portopulmonary hypertension; MPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; PCWP, pulmonary capillary wedge pressure.

  • *

    Microbubbles were detected in the left atrium between three and six cardiac cycles after visualization of microbubbles in the right atrium.

  • Measurements via right heart catheterization. Absolute inclusion criteria for the database required a combination of 1, 2, and 3. Although most patients had PCWP ≤ 15 mm Hg, a subgroup of patients that had PCWP > 15 mm Hg were recognized separately (see text).

1)Liver disease that meets minimal listing criteria for liver transplantation; and
2)PaO2 < 70 mm Hg or alveolar-arterial oxygen gradient > 20 mm Hg; and
3)Pulmonary vascular dilatation documented by either  a) “positive” contrast enhanced transthoracic echo*; or  b) brain uptake > 6% following lung perfusion scanning with 99mTc macroaggregated albumin
1)Liver disease that meets minimal listing criteria for liver transplantation; and
2)MPAP ≥ 25 mm Hg; and
3)PVR ≥ 120 dynes.s.cm−5; and
4)PCWP ≤ 15 mm Hg

Patient Selection Definitive Outcomes

Any patient evaluated at one of the participating liver transplant centers and otherwise considered to be a liver transplant candidate was eligible (met minimal listing criteria or institutional criteria) to be entered into the database. No patient with HPS or PortoPH was excluded if a definitive outcome was documented and key variable data were submitted. Definitive outcomes were defined by 1 of 3 mutually exclusive categories: (1) denied OLT (primary reason for denial provided); (2) accepted for OLT, underwent transplantation, and survived transplant hospitalization; and (3) accepted for OLT, underwent transplantation, but died during the transplant hospitalization (2 mortality subgroups: intraoperative death; survived OLT procedure, but died during same hospitalization.

Key Variables of HPS

Pre-OLT oxygenation data from patients with HPS were obtained by measuring arterial blood gases with the patient breathing room air in the sitting position at rest. These data included PaO2, pH, and PCO2. Alveolar-arterial oxygen gradients were not computed because of the difficulty in standardizing calculations determining alveolar oxygen partial pressures among contributing centers.

Key Variables of PortoPH

Pre-OLT pulmonary hemodynamic data from patients with PortoPH were obtained during right heart catheterization in a clinically stable condition. Measurements included mean pulmonary artery pressure (MPAP) (in millimeters of mercury), mean right atrial pressure (in millimeters of mercury), cardiac output (CO) (in liters/minute using the thermodilution method), pulmonary capillary wedge pressure (PCWP) (in millimeters of mercury), and calculated pulmonary vascular resistance (PVR). PVR was calculated using the standard formula:7

equation image

Corrections for body surface area (and subsequent calculations of indices for CO and PVR) were not uniformly submitted. Reasons for transplant denial and causes of death were categorized by primary and secondary reasons. No patient follow-up was conducted for those who were denied OLT or those who survived the transplant hospitalization.

Statistical Analysis

All data were reported as means ± 1 SD. Comparison of means was conducted using the Mann-Whitney and Kruskal-Wallis tests for independent samples. Pairwise comparisons using Bonferroni correction for multiple comparisons were accomplished where appropriate. A P value less than .05 was considered statistically significant.


Selected demographics and specific hepatic diagnoses associated with either HPS (n = 40) or PortoPH (n = 66) are summarized in Table 2. All patients were considered to be liver transplant candidates (i.e., met minimal listing criteria as defined by Child-Turcotte-Pugh scores or institutional standards). Severity of liver disease (by outcome subgroups) was characterized using Child classes (A, B, or C) and mean values of variables that comprise the Model End-Stage Liver Disease score (serum bilirubin, serum creatinine, and international normalized ratio) (Table 3). Severity of liver disease was not significantly different in the subgroups' outcomes. In regard to the acuity of liver disease, no patient in the database had a diagnosis of acute hepatic failure.

Table 2. Demographics and Frequency of Liver Disease Diagnoses
 HPS PortoPH 
  • Abbreviations: HPS, hepatopulmonary syndrome; PortoPH, portopulmonary hypertension; pts, patients; EtOH, ethanol; HCV, hepatitis C virus; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; NASH, nonalcoholic steatohepatitis.

  • *

    All pediatric patients (age < 18 years).

  • †One pediatric patient.

Total (N) 40 66 
Female 50% 47% 
Pediatric pts (n)16 0 
 (age yr range) 6-18  
Adult pts (n) 24 66 
 (age yr range) 19-67 29-67 
Mean age yr (all pts)37 50 
Biliary atresia15*  
Cryptogenic cirrhosis6 9 
Hepatitis C disease4 11 
Alcoholic cirrhosis6 25 
 Etoh alone 4 15
 Etoh + HCV 2 10
PBC 8 
 alone  3
 PBC + auto  5
Autoimmune hepatitis3** 3 
NASH2 1 
PSC1 2 
Noncirrhotic portal hypertension 1 
Hepatitis B/D 2 
Alpha1 antitrypsin ZZ phenotype 1 
Other2 3 
Table 3. Severity of Liver Disease
  • Abbreviations: HPS, hepatopulmonary syndrome; PortoPH, portopulmonary hypertension; NR, not reported; INR, international normalized ratio.

  • *

    No significant differences between outcome subgroups.

Childs A117612
Childs B441513611
Childs C33947
Mean bilirubin (mg/dl)*4.0 ± 0.97.4 ± 2.95.5 ± 1.44.1 ± 3.95.5 ± 6.36.8 ± 11.2
Mean creatinine (mg/dl)*1.9 ± 1.10.3 ± 00.7 ± 0.31.0 ± 0.11.5 ± 0.41.1 ± 0.1
Mean INR*1.4 ± 0.21.7 ± 0.41.4 ± 0.31.5 ± 0.11.8 ± 0.31.2 ± 0.1

Entire Group With HPS

Mean PaO2 was 51 ± 10 mm Hg (range 29–70 mm Hg). Severe hypoxemia (PaO2 < 50 mm Hg) was documented in 20 of 40 patients (50%). Mean pH was 7.46 ± .03 (range 7.40–7.55); mean PaCO2 was 30 ± 5 mm Hg (range 22–40 mm Hg).

Patients With HPS Who Were Denied OLT

Eight of 40 patients (20%) with HPS were denied OLT. Mean PaO2 was significantly less in patients with HPS who were denied OLT than in patients who underwent OLT (47 vs. 52 mm Hg; P < .005). The primary reason for denial was nonpulmonary in all 8 cases and included coronary artery disease (3), age (2), renal insufficiency (2), and hepatocellular cancer (1).

OLT Survivors With HPS Versus Nonsurvivors

In most cases, the pretransplant PaO2 determinations were made within 12 months before transplantation. Thirty-two of 40 patients (80%) with HPS underwent OLT. No intraoperative deaths occurred. Mortality during the transplant hospitalization occurred in 5 of 32 patients (15.6%). Pretransplant mean PaO2 was significantly less in nonsurvivors (37 ± 8 mm Hg) compared with survivors (55 ± 11 mm Hg; P < .005).

The length of hospital stay was 5 to 167 days (median 10 days) for adult survivors and 5 to 215 days (median 68 days) for pediatric survivors. The causes of death (18–262 days post-OLT) in the 5 patients were as follows: gastrointestinal sepsis (in 1 adult patient) and rejection hepatic artery thrombosis, portal vein thrombosis, and biliary leak sepsis (in 4 pediatric patients). Pretransplant mean PaO2 comparisons are summarized in Table 4. Pediatric intubation and mechanical ventilation were necessary for a median of 2 days (range 1–17 days), and median hospital length of stay was 74 days (range 20–266 days). Adult intubation and mechanical ventilation were needed a median of 1 day (range 1–25 days), and median length of hospital stay was 15 days (range 8–167 days).

Table 4. Pre-OLT PaO2 in HPS Patients
 All HPS N = 40Denied OLT n = 8Transplant
Survivors* n = 27Nonsurvivors* n = 5
  • Abbreviations: OLT, orthotopic liver transplantation; PaO2, partial pressure for arterial oxygen; HPS, hepatopulmonary syndrome.

  • *

    Significant difference between groups via Kruskal-Wallis test (P = 0.005).

PaO2 (mm Hg)51 ± 1047 ± 1055 ± 1137 ± 8
Range (mm Hg)(29-70)(35-47)(34-70)(29-47)

The Entire Group With PortoPH

Mean MPAP was 48 ± 11 mm Hg (range 25–86 mm Hg), mean CO was 7.3 ± 3.1 L/min (range (2.5–17.0 L/min), mean PCWP was 11 ± 6 mm Hg (range 4–32 mm Hg), mean PVR was 462 ± 202 dynes · s · cm−5(range 127–1,354 dynes · s · cm−5), and mean right atrial pressure was 10 ± 6 mm Hg (range 1–30 mm Hg). Twelve patients had PCWP ranging from 16 to 32 mm Hg, but each had abnormal transpulmonary gradients (MPAP and PCWP > 15 mm Hg) ranging from 17 to 50 mm Hg and PVR ranging from 133 to 545 dynes · s · cm−5.

Moderate PortoPH (35 ≤ MPAP ≤ 50) occurred in 34 of 66 patients (52%); severe PortoPH (MPAP ≥ 50 mm Hg) was documented in 25 of 66 patients (38%). PVR greater than 250 dynes · s · cm−5 was noted in 44 of 60 patients (73%). The diagnosis of PortoPH was established intraoperatively in 2 of 36 patients (6%) who underwent transplantation (both subsequently died).

Screening with transthoracic Doppler echocardiography was conducted in 64 of 66 patients (97%). Estimates of right ventricular systolic pressure (RVsys) by echocardiography were obtained in 52 of 64 patients (81%). In the 12 patients without RVsys estimates, dilated right ventricles were documented in 4 patients; qualitative description was not reported in 8 patients. Six of those 8 patients died during the transplant hospitalization. Of the 52 patients who had RVsys determined by Doppler echocardiography (all had PortoPH by hemodynamic criteria), screening echo RVsys was greater than 50 mm Hg in 47 of 52 patients (90%); RVsys was greater than 40 mm Hg in 50 of 52 patients (96%), and RVsys was greater than 30 mm Hg in 51 of 52 patients (98%). One patient had an RVsys of 26 mm Hg yet had a MPAP of 39 mm Hg, indicating that the screening echo significantly underestimated the hemodynamic problem.

Patients With PortoPH Who Were Denied OLT

Thirty of 66 patients (45%) were deemed inappropriate for OLT. In each case, patients were denied OLT because of the degree of pulmonary hypertension. Patients who were denied OLT had significantly higher MPAP (53 ± 11 mm Hg [range 39–86 mm Hg] vs. 45 ± 11 mm Hg [range 25–74 mm Hg]); P < .015) and PVR (614 ± 288 dynes · s · cm−5 [range 142–1,354 dynes · s · cm−5] vs. 335 ± 159 dynes · s · cm−5 [range 127–695 dynes · s · cm−5]; P < .005) than those who underwent transplantation. Neither CO (mean 6.2 ± 1.6 L/min; range 2.5–14.6 L/min) nor mean right atrial pressure was significantly different between the groups. No patient was denied OLT if MPAP was less than 35 mm Hg. Four patients who were denied transplantation had a PCWP greater than 16 mm Hg (17, 32, 20, and 20 mm Hg); each had increased MPAP (55, 58, 52, and 60 mm Hg) with increased PVR (454, 142, 548, and 456 dynes · s · cm−5), respectively.

OLT Survivors With PortoPH Versus Nonsurvivors

The mean time from right heart catheterization to OLT was 5.5 months (range 1–17 months). There were 13 deaths (36%) in the 36 patients who underwent transplantation. Five of the 13 deaths (38%) were intraoperative. In 4 patients, acute right heart failure developed with hypotension and cardiovascular collapse. One patient had an uncontrollable gastrointestinal bleed with subsequent hypotension and cardiac arrest. The 8 remaining deaths occurred by day 18 post-OLT. Major contributing causes of death were progressive right heart failure (3 patients), adult respiratory distress syndrome (2 patients), pulmonary hemorrhage (2 patients), myocardial infarction (2 patients), sudden cardiac death (1 patient), and renal failure (1 patient) (Table 5). Three patients had more than 1 major problem. Intubation and mechanical ventilation were necessary for a median of 1 day (range 1–90 days). The median length of transplant hospitalization was 16 days (range 6–92 days).

Table 5. PortoPH Pulmonary Hemodynamics of Patients Who Underwent Liver Transplantation
PtMPAP (mm Hg)PVR (dynes. s.cm−5)CO (l/min)RAP (mm Hg)Comments
  1. Abbreviations: PortoPH, portopulmonary hypertension; Pt, patient; MPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; CO, cardiac output; RAP, right atrial pressure; NR, not reported; dx, diagnosed; intraop, intraoperative; epopros, epoprostenol.

Died during transplant hospitalization
1323205.0NRDied Day 18
2363086.06Intraop death
3574347.0NRIntraop death
44018013.2NRIntraop death
5412506.4NRDied Day 4
64515115.011Died Day 8
75016017.010Died Day 3
8353305.63Intraop death
9375804.16Died Day 16
10544447.78Died Day 2/ preop epopros
1174NRNRNRDied Day 7/ Intraop dx
125822510.24Died Day 9/ Intraop dx
13444915.76Intraop death
Survived transplant hospitalization
36669513.9NRPreop nifedipine
4374205.9NRPreop nifedipine
5393146.4NRPreop prostacyclin
6384084.5NRPreop epopros
14606625.89Preop epopros
20353106.715Preop epopros
23446724.5NRPreop epopros

A comparison of pulmonary hemodynamics (survivors vs. nonsurvivors) are summarized in Table 6. There were no significant differences among mean MPAP, CO, PVR, and mean right atrial pressure. Only 1 of the 13 nonsurvivors received pretransplant prostacyclin (intravenous epoprostenol for 3 months); 5 of 23 survivors received long-term pre-OLT prostacyclin (up to 30 months). The use and duration of pre- or post-OLT or intraoperative prostacyclin were too variable to quantify.

Table 6. Mean Pre-OLT Pulmonary Hemodynamics in PortoPH Patients
ParameterAll PortoPH N = 66Denied OLT N = 30Transplanted
Survivors N = 23Nonsurvivors N = 13
  • Abbreviations: OLT, orthotopic liver transplantation; PortoPH, portopulmonary hypertension; MPAP, mean pulmonary artery pressure (mm Hg); PVR, pulmonary vascular resistance (dynes.s.cm−5); CO, cardiac output (L /min); RA, mean right atrial pressure (mm Hg); PCWP, pulmonary capillary wedge pressure (mm Hg).

  • *

    P < 0.015 when compared to transplanted patients.

  • P < 0.005 when compared to transplanted patients.

MPAP48 ± 1153 ± 11*45 ± 1444 ± 8
PVR462 ± 202614 ± 288341 ± 181322 ± 139
CO7.3 ± 3.16.2 ± 3.38.2 ± 2.78.6 ± 4.3
RA10 ± 611 ± 78 ± 37 ± 3
PCWP11 ± 610 ± 611 ± 514 ± 6

In terms of pulmonary hemodynamic subgroups, Table 7 summarizes the outcomes based on the previously described subgroups. Of the patients who died during the transplant hospitalization mortality, 12 of 13 (92%) had a pretransplant MPAP greater than 35 mm Hg; mortality was associated with a PVR greater than 250 dynes · s · cm−5 in 8 of 13 patients (62%).

Table 7. PortoPH: Outcome and Pulmonary Hemodynamic Subgroups (Untreated)
 Denied OLT (N = 30)Following OLT:
Died (N = 13)Survived (N = 23)
  1. Abbreviations: PortoPH, portopulmonary hypertension; OLT, orthotopic liver transplantation; MPAP, mean pulmonary artery pressure (mm Hg); PVR, pulmonary vascular resistance; NR, not reported.

MPAP < 35015
 PVR ≤ 250005
 PVR > 250010
 PVR NR000
35 ≤ MPAP ≤ 5015812
 PVR ≤ 250133
 PVR > 2501259
 PVR NR200
50 < MPAP1546
 PVR ≤ 250110
 PVR > 2501324
 PVR NR112

Five of the 13 deaths (38%) were associated with increased PCWP (19, 21, 17, 16, and 28 mm Hg), increased MPAP (57, 41, 45, 50 and 58 mm Hg), and abnormal PVR (437, 262, 149, 160, and 240 dynes · s · cm−5). Two of these patients had markedly elevated serum creatinine levels (3.2 and 3.7 mg/dL). Left ventricular ejection fractions ranged from 55% to 74%.

Patterns of outcome by specific transplant center are summarized in Table 8.

Table 8. Outcomes by Transplant Center
CenterHPS TxPortoPH Tx
  • Abbreviations: HPS, hepatopulmonary syndrome; PortoPH, portopulmonary hypertension; Tx, transplantation.

  • *

    Three patients not included in these totals died while on the OLT waiting list (see text).



The data collected from this multicenter effort of several centers described the relationship among preoperative arterial oxygenation in patients with HPS, preoperative pulmonary hemodynamics in patients with PortoPH, and liver transplant outcome. Outcomes were categorized as (1) denied transplant, (2) died during transplant hospitalization, and (3) survived transplant hospitalization. We chose to address these specific outcomes from the perspective of “key” variables that have been reported and emphasized in previous studies concerning HPS,2–4, 7 PortoPH,5, 6, 10–12 and liver transplantation.2, 3, 5–7

The relationship between attributes of HPS, PortoPH, and denial of liver transplantation reflects physician judgment and current medical thinking. We found that some, but not all, patients with the greatest severity of pulmonary vascular complications of portal hypertension, as measured by specific parameters for oxygenation and pulmonary hemodynamics, were excluded from transplant consideration. Such preselection of patients (and comorbidities in the case of patients with HPS) presumably eliminated patients with the highest reported factors for mortality from subsequent OLT.

Patients with HPS who were denied liver transplantation had lower PaO2 values than those who proceeded to OLT. In each case, however, physicians reported reasons other than significant hypoxemia for denying OLT. It is possible that significant hypoxemia influenced physicians' decisions to proceed to OLT. There was a small but statistically significant difference in PaO2 between patients who were denied and who underwent liver transplantation. The clinical significance of that difference is arguable. Even with the exclusion of some, but not all, patients with severe hypoxemia before OLT, our data indicated a relationship between the severity of hypoxemia and transplant hospitalization mortality, supporting previous limited experience.2–4 PaO2 measured while breathing 100% oxygen was not associated with increased post-OLT mortality.7 Variable institutional methods to obtain 100% PaO2 (face mask vs. nose clip with sealed mouthpiece) complicated the reliability and interpretation of data reported and precluded their inclusion in this analysis.

There are no proven pre-OLT medical treatments for HPS, and mortality for those who do not undergo liver transplantation is significant. Recent data indicate 50% survival 41 months after the diagnosis of HPS.9 Correcting hypoxemia by increasing PaO2 with supplemental oxygen (easy to do) appears simplistic. However, supplemental nasal cannula oxygen (during rest, exercise, and sleep) to maintain satisfactory hemoglobin saturations before OLT improves the symptoms of dyspnea and fatigue. The role of abnormal oxygenation in the development of biliary and gastrointestinal sepsis or central nervous system events should not be underestimated. Worsening post-OLT oxygenation in the setting of HPS has been improved by using inhaled nitric oxide13, 14 and Trendelenburg body positioning.15 The goal is to improve pulmonary ventilation and perfusion matching (by selective pulmonary vasodilatation and shifting blood flow, respectively) that may evolve because of excess fluid and/or atelectasis.13 There is no doubt that the occurrence of nonpulmonary events in the perioperative period in the setting of hypoxemia presents management challenges. Recent data indicate that the combination of PaO2 and brain uptake after lung perfusion scanning with technetium-labeled macroaggregated albumin may be of prognostic importance.7 Long-term post-OLT supplemental oxygen is expected in these patients, and the duration correlates well with the severity of pre-OLT hypoxemia.4

A different pattern of OLT denial was observed in patients with PortoPH. The primary reason for OLT denial in each patient was the severity of pulmonary hypertension as measured by MPAP and PVR. Indeed, mean MPAP and PVR were significantly worse in those denied OLT compared with patients who underwent transplantation. Prior data indicate that such cases may not have been excluded from OLT consideration in the past and, indeed, did quite poorly.6 Approximately 65% of previously reported cases of PortoPH were first diagnosed in the operating room at the time of transplant.7 Our current data may reflect progress in the area of detection; only 2 cases were first diagnosed during the transplant hospitalization, but both patients died during the transplant hospitalization (Table 5). Our data support the previous observations that MPAP greater than 35 mm Hg and PVR greater than 250 dynes · s · cm−5 are associated with increased post-OLT mortality.6

Patients with increased MPAP, PVR, and PCWP remain problematic in terms of classification and present frequently (12/66 [18%] in this study). Five of those patients died (2 had abnormal renal function as a comorbidity). In addition to increased PVR, each patient had increased transpulmonary gradient, indicating resistance to arterial flow. The prognostic significance of an increased transpulmonary gradient remains to be determined, and careful study of right and left ventricular function is warranted in this group. Other than left ventricular ejection fractions, this data collection did not address more extensive left ventricular study (nor were additional data such as coronary artery angiography descriptions reported).

Screening for PortoPH by transthoracic Doppler echocardiography was conducted in the majority of patients entered into this database. This clinical practice was strongly supported by participants in the 2003 Third World Symposium on Pulmonary Artery Hypertension.16 However, right heart catheterization remains the definitive diagnostic study, noting that in approximately 20% of patients reported, RVsys could not be accurately determined. In addition, RVsys greater than 50 mm Hg has correlated poorly with the actual severity of pulmonary hypertension determined by right heart catheterization.17

Pre-OLT treatments reported for the treatment of PortoPH were somewhat surprising. There seemed to be an infrequent use of the pulmonary vasodilator prostacyclin as a means to improve pulmonary hemodynamics, especially in those who did not survive the transplant hospitalization. Acute and long-term benefit of intravenous epoprostenol has been demonstrated.10–12 Intravenous epoprostenol was used in only 5 of the 23 patients (22%) with PortoPH who survived OLT. It is instructive to observe that all reported deaths occurred by day 18 posttransplant and that only 1 patient had used intravenous epoprostenol for a prolonged time (3 months) before OLT. The optimum pre-OLT treatment of PortoPH remains problematic in that mortality occurs as the result of either hepatic or right heart failure events.12 Earlier treatment with pulmonary vascular therapies followed by OLT seems logical and may have significant survival implication.12

Limitations of this voluntary effort are obvious, and several points should be emphasized. First, reporting bias existed in the sense that institutions submitted patient data that reflected center volumes, referral bias, and center experience with HPS or PortoPH. Second, our selection of key variables for data analysis reflected the experience of many transplant centers; indeed, other variables not routinely collected may be of prognostic importance. Third, adverse data were voluntarily reported to this database. We still have a weak understanding concerning the specific adverse events that follow OLT attempts in patients with HPS and PortoPH in that no required, uniform data-reporting mechanism for these entities is in place. Fourth, the events that occur intraoperatively, especially in the setting of PortoPH, were not adequately addressed in this data collection. Fifth, the role of prostacyclin in the pre-OLT and perioperative treatment of PortoPH was poorly standardized and confounded the positive effect (and analysis) of that treatment approach. Finally, long-term follow-up was not part of the accomplishment of this database. Preliminary data indicate that a beneficial outcome for patients with HPS and PortoPH if OLT can be successfully accomplished.8, 9 We have strong empiric evidence that HPS can completely resolve and rarely recur; the outcome of PortoPH (subsequent resolution of abnormal pulmonary hemodynamics) is much less clear.

Can we advise a practice management consensus on the basis of the voluntary and incomplete nature of the data reported? There were no specific criteria followed between institutions that would guide referral or refusal for transplant consideration. We chose to simply summarize the measurable parameters usually assessed (for HPS and PortoPH) and relate those data to predefined outcome. We recognize that other variables and considerations may enter into the OLT selection process when pulmonary vascular disorders occur in the OLT candidate.


These pulmonary vascular consequences of advanced liver disease remain significant clinical challenges. Identification and management will continue to present problems for pulmonologists, anesthesiologists, hepatologists, and surgeons in centers conducting liver transplantation. Significant transplant hospitalization mortality associated with HPS and PortoPH continues despite improved screening and patient selection. Ideal pretransplant treatment of PortoPH remains problematic. Additional efforts to quantify the impact and consequences of HPS and PortoPH on OLT should continue.